Model Organisms in Drug Discovery

154 MECHANISM OF ACTION IN MODEL ORGANISMS
6.1 Introduction
How is it that drugs work? What is the mechanism by which they are able to
alter disease processes inside the human body? Most drugs are composed of
small organic compounds in pill form that are swallowed and absorbed
through the stomach or small intestine. The molecules then permeate the body
by riding along in the bloodstream until they find their targets and modulate
its activity. The targets of most drugs are the cellular proteins that carry out
most functions within our bodies. For instance, one particular subset of
proteins, the G-protein-coupled receptors, are the targets of more than onethird
of the drugs on the market today, representing 30% of the top-selling
pharmaceuticals (Scussa, 2002). Given that drugs target proteins, some of
which belong to the same subset, how is it that these compounds have specific
effects? Generally speaking, the drugs presently available have undergone a
rigorous selection process. This process aims to ensure that they target only
the specific proteins or cellular function involved in a given disease and not
others necessary for the normal functions of human cells. Occasionally,
however, drugs may need to change the activity of more than one protein to be
effective, or may cause unwanted effects because they are not specific enough.
In addition, sometimes the proteins targeted by the drug are unknown. In
these cases it is very important to identify the compound’s target and therefore
to understand the mechanism by which small molecules affect biological
processes (Koh and Crews, 2002). Aptly, these types of studies are termed
mechanism of action (MOA) and traditionally use a variety of biochemical
assays to find the direct binding partners to a compound; however, model
system genetics are proving useful for identifying the function of the
compound’s biology. Invertebrate models systems such as Caenorhabditis
elegans and Drosophila are ideal for studying compounds and ultimately in
identifying the protein target(s). In theory, MOA studies in living systems are
only limited by the specificity and bioavailability of the drug in question. The
objective of this chapter is to explore the need for MOA studies and the
genetic systems in which they are effective, utilizing specific examples.
6.2 Introduction to compound development
In order to understand the need for MOA technologies in pharmaceutical
companies, one must take a closer look at the process by which drugs have
been developed. Some of the earliest records of drug discovery come from
ancient times. Their methods of drug discovery were mostly in vivo, with in
vivo in this case meaning not animal models but rather humans eating,
drinking or topically applying crude extracts from one or several plants,
animal venoms, secretions or parts. In what can only be classified as ‘trial and